On the Nature of Nucleobase Stacking in RNA: A Comprehensive Survey of Its Structural Variability and a Systematic Classification of Associated Interactions

Abstract

The astonishing diversity in folding patterns of RNA threedimensional (3D) structures is crafted by myriads of noncovalent contacts, of which base pairing and stacking are the most prominent. A systematic and comprehensive classification and annotation of these interactions is necessary for a molecular-level understanding of their roles. However, unlike in the case of base pairing, where a widely accepted nomenclature and classification scheme exists in the public domain, currently available classification schemes for base−base stacking need major enhancements to comprehensively capture the necessary features underlying the rich stacking diversity in RNA. Here, we extend the previous stacking classification based on nucleobase interacting faces by introducing a structurally intuitive geometry-cum topology-based scheme. Specifically, a stack is first classified in terms of the geometry described by the relative orientation of the glycosidic bonds, which generates eight basic stacking geometric families for heterodimeric stacks and six of those for homodimeric stacks. Further annotation in terms of the identity of the bases and the region of involvement of purines (five-membered, six-membered, or both rings) leads to the enumeration of 384 distinct RNA base stacks. Based on our classification scheme, we present an algorithm for automated identification of stacks in RNA crystal structures and analyze the stacking context in selected RNA structures. Overall, the work described here is expected to greatly facilitate the structure-based RNA research.

Molecular Dynamics Simulations of the Aptamer Domain of Guanidinium Ion Binding Riboswitch ykkC-III: Structural Insights into the Discrimination of Cognate and Alternate Ligands

“…In addition, we visually identified and characterized all types of stacking interactions present in the crystal structure (Figure B) and during simulations (Tables S18–S21) using the “Stack Detector” web portal () . This tool detects stacking interactions using a 5 Å cut off for the center-to-center distance of the nucleobase rings, a 23° cut off for the tilt angle between the nucleobase rings, and 40° for the dihedral angles representing the horizontal displacement of one nucleobase ring with respect to the other, within a stack .…”

“…(A) Hydrogen-bonding (base-pairing) interactions represented using the Leontis–Westhof symbols and (B) stacking interactions between the residues deduced from the crystal structure of the aptamer domain of the ykkC -III riboswitch bound to the guanidinium cation ligand (PDB code: 5NWQ) represented using the recently proposed symbols . Specifically, arrows represent different stacking types based on the faces of nucleobases ( ≫ upward, ≪ downward, >< inward, and <> outward).…”

Challenges with Simulating Modified RNA: Insights into Role and Reciprocity of Experimental and Computational Approaches

“…Base pairing can occur in different orientations based upon which ‘edge’ of the nucleobase is involved in the pairing [ 26 ]. Base stacking contributes to duplex formation as well as the stability of a folded RNA [ 27 , 28 ]. RNA modifications contribute to either enhanced, reduced, or altered base pairing and stacking preferences, conformational flexibility, helical winding, groove hydrophobicity and polarity, and stability of tertiary and long-range interactions [ 1 , 22 , 29 ].…”

Exploring the Nature of Hydrogen Bonding between RNA and Proteins: A Comprehensive Analysis of RNA : Protein Complexes

“…Noncovalent interactions are specifically suited for biomolecular recognition. Owing to their importance, a significant number of studies in the last decade have analyzed the distribution of noncovalent interactions involved in biomolecular recognition [4–11] …”

“…Owing to their importance, a significant number of studies in the last decade have analyzed the distribution of noncovalent interactions involved in biomolecular recognition. [4][5][6][7][8][9][10][11] RNA : protein recognition is a specific type of biomolecular recognition that encompasses a wide variety of processes, [12] such as ribosomal function (e. g., interaction of ribosomal protein factors with rRNA), [13] transcription (i. e., interaction of RNA polymerases with mRNA), [14] tRNA loading (i. e., interaction of tRNA with aminoacyl tRNA synthetases), [15] and the interaction of proteins with ribonucleotide (rN) cofactors for their catalytic function. [9] Thus, not surprisingly, significant literature has been devoted towards assessment of the distribution of noncovalent interactions in RNA : protein complexes.…”